The present invention concerns methods and systems for treatment of restenosis in body lumens such as blood vessels and, in particular, the treatment of in-stent restenosis.
Endoluminal stents are commonly used to treat obstructed or weakened body lumens, such as blood vessels and other vascular lumens. Numerous stents exist for this purpose, including those made of metals, fibers and other biocompatible materials. In general, the stent is either formed outside the body and then guided into place (e.g., adjacent to an obstruction) through a body lumen, or is positioned into place prior to formation and is then expanded and/or formed in situ within the body lumen. Once deployed, the stent can remain in the body lumen where it will maintain the patency of the lumen and/or support the walls of the lumen which surround it.
One factor impeding the success of stent technology in endoluminal treatments is the frequent occurrence of in-stent restenosis, characterized by proliferation and migration of smooth muscle cells within and/or adjacent to the implanted stent, causing reclosure or blockage of the body lumen. While the reasons for such smooth muscle cell proliferation following stent implantation are not entirely clear, it is believed that positioning of the stent within the body lumen may somehow irritate or damage the surrounding lumen walls and activate medial smooth muscle cells lining the walls.
Current methods for treating endoluminal restenosis, such as that which occur within or around a stent, generally consist of invasive procedures which physically remove atherosclerotic plaque by, for example, shaving or ablating the plaque, or by implanting a second stent. However, these procedures can cause further damage to the area of treatment and/or initiate further smooth muscle cell proliferation.
Accordingly, it is an object of the present invention to provide a substantially non-invasive method of treating in-stent restenosis by applying radiation to the smooth muscle cells which have grown within or around a stent implant in a manner that does not substantially damage the surrounding lumen wall or the stent itself, while resulting in a reduction of smooth muscle cell mass.
Methods and systems are disclosed for treating in-stent restenosis using radiation having a wavelength sufficient to kill or promote cellular death (e.g., through programmed cell death), or otherwise remove smooth muscle cells which have proliferated, or which might otherwise proliferate, in the proximity of (i.e., within, around or adjacent to) a stent within a body lumen, causing (or potentially causing) at least partial blockage of the lumen. Devices are disclosed for providing such therapeutic radiation at the stent with or without concurrent mechanical (e.g. balloon dilation) angioplasty. Treatment methods are also disclosed which include irradiating smooth muscle cells in the region of the stenosis with non-ablative, cytotoxic radiation, such as UV radiation. A cytotoxic, photoactivatable chromophore may also be delivered to the treatment site prior to irradiation. The methods and systems can be used prophylactically or to treat in-stent restenosis after blockage has occurred without further damage to surrounding tissue.
In-stent restenosis can be treated effectively and with minimal tissue damage using cytotoxic, nonablative radiation, such as UV radiation. The radiation kills or otherwise inactivates smooth muscle cells which have proliferated or are susceptible to proliferation within and/or adjacent to a stent in a body lumen, causing the cells to retract from the stenosed region. The radiation is preferably delivered to the area around (e.g., within or adjacent to) the stent via an optical fiber or other waveguide incorporated, for example, into a percutaneous catheter.
The term xe2x80x9cin-stent restenosis,xe2x80x9d as used herein, includes partial or complete blockage of a body lumen in an area of stent implantation due in whole or in part to proliferation of medial smooth muscle cells within or around (e.g., adjacent to) the stent. The term xe2x80x9ccell overgrowthxe2x80x9d as used herein is intended to describe any condition involving the proliferation of cells in proximity to a stent. The term xe2x80x9cbody lumen,xe2x80x9d as used herein, includes any body lumen capable of containing a stent, such as vascular, urological, biliary, esophageal, reproductive, endobronchial, gastrointestinal, and prostatic lumens. The term xe2x80x9cnon-ablative, cytotoxic radiation,xe2x80x9d as used herein, means radiation which directly or indirectly (e.g., by apoptosis) kills or otherwise causes the removal of smooth muscle cells in a stenosed region, resulting in a reduction in tissue mass and/or an increase in the diameter of the lumen, without the use of heat ablation.
In one embodiment of the invention, the cytotoxic, non-ablative radiation is ultraviolet (UV) radiation having a wavelength of less than about 280 nanometers, down to about 240 nanometers (due to the limited transmission efficiency of glass optical fibers at lower wavelengths). The effect of UV radiation having this wavelength range, commonly known as UV xe2x80x9cCxe2x80x9d radiation, at the doses necessary to penetrate the build up of smooth muscle cell mass, causes direct cellular death of most cells and can cause programmed cell death in other cells, resulting in a reduction in cell mass without heating or damaging the surrounding tissue.
In another embodiment of the invention, the cytotoxic, non-ablative radiation has a longer wavelength, such as UV xe2x80x9cAxe2x80x9d or xe2x80x9cBxe2x80x9d radiation in the wavelength range of about 280 nanometers to 400 nanometers, or visible radiation having a wavelength of about 400 to 700 nanometers, or infrared radiation from about 700 nanometers to 2.6 micrometers, and is used in conjunction with a photoactivatable, cytotoxic chromophore which is activated upon exposure to light at some or more of these wavelengths. The term xe2x80x9cphotoactivatable, cytotoxic chromophore,xe2x80x9d as used herein, encompasses chromophores capable of being absorbed by mammalian tissues and being activated upon exposure to light so cells of the tissue die or cease to proliferate. In the present invention, the photoactivatable chromophore is delivered to tissue which has increased in mass (e.g., due to smooth muscle cell proliferation) within or around a stent and is causing restenosis of the lumen supported by the stent. The tissue is then exposed to radiation of a sufficient wavelength to activate the chromophore. Once activated by the light, the chromophore causes direct programmed death (apoptosis) thereby decreasing the number of cells and the mass of the tissue.
Suitable chromophores for use in the invention are generally selected for absorption of light that is deliverable from common radiation sources (e.g. UV light ranging from 240-400 nanometers, or visible light having wavelengths of 400 nanometers or longer). For example, photoactivatable psoralens and hematoporphyrins can be administered systemically or locally to the stenosed region prior to irradiation, thereby rendering smooth muscle cells in the region more susceptible to radiation. Other suitable chromophores are well known in the art and include those which are photoactivated upon irradiation with either long-wave UV light (PUVA) (See, e.g., U.S. Pat. No. 5,116,864 (March et al.) or with visible light (see, e.g., U.S. Pat. No. 5,514,707 (Deckelbaum et al.), the disclosures of which are incorporated herein by reference.)
Various radiation sources can be use in accordance with the present invention to deliver non-ablative, cytotoxic radiation to a stenosed region within or around a stent. Generally, the radiation is delivered via a laser catheter carrying a fiber optic waveguide. Either pulsed or continuous wave (xe2x80x9cCWxe2x80x9d) lasers can be used in the present invention, and the lasant medium can be gaseous, liquid or solid state. The laser can be a pulsed excimer laser, such as a KrF laser. Alternatively, rare earth-doped solid state lasers, ruby lasers and Nd:YAG lasers can be operated directly or in conjunction with frequency modification means to produce an output beam at the appropriate radiation wavelength (e.g., UV wavelength). Alternatively, a UV flash lamp can be employed.
In one embodiment, a laser system which operates at about 266 nanometers is used to maximize the cytotoxic effect of the radiation. This may be achieved using an output beam wavelength of about 266 nanometers or, alternatively, using an output beam wavelength of about 1064 nanometers, such as a common Nd:YAG laser, in conjunction with two doubling crystals to yield a radiation output of about 266 nanometers. Similarly, a Nd:YLF laser operating at about 1047 nanometers can be used in conjunction with two frequency doubling crystals. Other useful UV radiation sources include, for example, Argon ion lasers emitting UV light at about 257 or 275 nanometers and KrF excimer lasers emitting light at about 248 nanometers.
In another embodiment of the invention, the cytotoxic, non-ablative radiation is provided by a xe2x80x9clow energyxe2x80x9d radiation source. The term xe2x80x9clow energyxe2x80x9d is used herein to describe both laser and non-coherent radiation systems having an energy output of less than about 5 J/cm2 per pulse for pulsed lasers, or a total dose of less than about 1000 J/cm2, more preferably less than 100 J/cm2, for continuous wave lasers or non-coherent radiation sources.
In general, when using conventional percutaneous catheters to deliver radiation, at least one optical fiber or waveguide is incorporated into the catheter for transmission and delivery of the radiation to the lesion (i.e., stenosed) site. For example, an optical fiber having about a 200 micron diameter core may be used. The catheter tip can also contain focusing optics or diffusive elements for use in directing the radiation emitted from the catheter within an artery. The therapeutic radiation can be provided by a single laser or a plurality of lasers operating in tandem to deliver cytotoxic, nonablative laser radiation.
Catheter systems useful in connection with the present invention may also be equipped with a translucent (light-conducting) balloon which encompasses the optical fiber(s) or other energy conducting means. One example of such an apparatus is disclosed in commonly-owned, U.S. Pat. No. 5,620,438 issued to Amplatz et al. on Apr. 15, 1997 and incorporated herein by reference. Once the catheter is guided into place within or adjacent to an area of restenosis associated with a stent, the balloon is inflated to dilate the surrounding tissue. Light is then delivered into the balloon via the optical fiber(s) and is transmitted through the balloon onto the surrounding tissue of the lumen walls. The balloon is preferably large enough in diameter to completely cover (i.e., come in contact with all portions of) the stenosed region. Preferably, the balloon is at least sized such upon inflation, it extends beyond the length of the stent by a distance sufficient to dilate any blockage within the stent. The light source (or sources) can likewise be chosen to extend beyond the stent by a sufficient distance to ensure treatment of the entire restenosis. In one illustrated embodiment, a 30 mm length balloon is inflated within a 20 mm stent overgrown (infiltrated) with smooth muscle cells. The balloon is inflated so that the entire interior of the stent is dilated and the distal ends of the balloon emerge from the stent.
The method of the present invention can be used to treat in-stent restenosis which has already occurred within or adjacent to a stent in a body lumen. The method provides the advantage of being substantially non-invasive and non-injurious compared to methods which physically remove or ablate endoluminal lesions.
The invention will next be described in connection with certain illustrated embodiments. However, it should be clear that various changes and modifications can be made by those skilled in the art without departing from the spirit or scope of the invention.